Target-activated cell/tissue-penetrating peptide for delivery of impermeable compounds and use thereof

Abstract

The present invention relates to a target-activated cell/tissue-penetrating peptide for delivery of impermeable compounds (Target Activated Cell/tissue Translocation peptide for Impermeable Compound Strategy (TACTICS)), and the use thereof, and more particularly to a target-activated cell/tissue-penetrating peptide, which comprises (a) a protein transduction domain (PTD), (b) a masking domain and (c) a spacer having a cleavage site specific for a target cell/tissue enzyme and is provided with target selectivity so as to penetrate specifically into a target tissue, and to a conjugate of the peptide with a drug or drug-containing particles for imaging or therapeutic applications. Because the target-activated cell/tissue-penetrating peptide has target selectivity, the peptide-drug conjugate exhibits maximized imaging and therapeutic effects, and the non-specific distribution of the conjugate in vivo is inhibited, so that the side effects of the conjugate are minimized, the diagnostic effects of the conjugate are maximized, and the conjugate is useful for the treatment of disease.

What is claimed is: 
     
       1. A target-activated cell/tissue-penetrating peptide-drug conjugate for delivery of impermeable compounds, wherein said target-activated cell/tissue-penetrating peptide includes:
 a protein transduction domain (PTD), wherein the protein transduction domain (PTD) consists of D-type or L-type amino acids, and contains any one or more amino acids selected from the group consisting of arginine, lysine and histidine in an amount of 70-80%, wherein the protein transduction domain (PTD) is low molecular weight protamine (LMWP); 
 a masking domain ionically bonded with the protein transduction domain (PTD), wherein the masking domain ionically bonded with the protein transduction domain (PTD) consists of D-type or L-type amino acids, and contains anionic amino acids in an amount of 70-100%, wherein the anionic amino acids include glutamic acid or aspartic acid, wherein the masking domain consists of 4-8 amino acids; and 
 a spacer connecting the protein transduction domain (PTD) with the masking domain and having a cleavage site specific for a target cell/tissue enzyme, wherein the spacer has a site which is cleaved by matrix metalloprotease (MMP), wherein the spacer consists of SEQ ID NO: 25 (PLGLAG), 
 wherein said target-activated cell/tissue-penetrating peptide-drug conjugate is prepared with a crosslinker selected from succinimidyl-4-[N-maleimidomethylcyclohexane-1-carboxy-[6-amidocaproate]] (SMCC) or its sulfonate (sulfo-SMCC). 
 
     
     
       2. The target-activated cell/tissue-penetrating peptide-drug conjugate according to  claim 1 , wherein the target-activated cell/tissue-penetrating peptide-drug conjugate comprises the drug which is conjugated at the protein transduction domain (PTD) of the target-activated cell/tissue-penetrating peptide. 
     
     
       3. The target-activated cell/tissue-penetrating peptide-drug conjugate according to  claim 2 , wherein the target-activated cell/tissue-penetrating peptide-drug conjugate comprises the drug which is conjugated at the protein transduction domain (PTD) by cysteine. 
     
     
       4. The target-activated cell/tissue-penetrating peptide-drug conjugate according to  claim 1 , wherein the drug is selected from the group consisting of anticancer agents, anticancer proteins, anti-inflammatory agents, anti-inflammatory proteins, immune enhancing proteins, bone resorption inhibitors, antisense oligonucleotides targeting the ribonucleic acid (RNA) of tumor or inflammatory disease proteins, and small interfering ribonucleic acids (siRNAs) targeting the RNA of tumor or inflammatory disease proteins. 
     
     
       5. The target-activated cell/tissue-penetrating peptide-drug conjugate according to  claim 4 , wherein the tumor or inflammatory disease proteins are selected from the group consisting of vascular endothelial growth factor (VEGF), B-cell leukemia/lymphoma 2 (BCL2), epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), Janus kinase (JAN), and phosphatidylinositol-3-kinase/Akt kinase (PI3-K/AKT). 
     
     
       6. A pharmaceutical composition comprising the target-activated cell/tissue-penetrating peptide-drug conjugate of  claim 4 .